Nearly four million patients in the U.S. carry the diagnosis of congestive heart failure and congestive heart failure represents the most common discharge diagnosis (DRG) at hospitals across the U.S. In 1995, the Healthcare Finance Commission spent over 15 billion dollars for the care of patients with the diagnosis of CHF. Since this represented only the medicare and medicaid populations, the cost burden to the commercial insurance industry was enormous.
Congestive heart failure is not a specific disease, but rather a compilation of signs and symptoms, all of which are caused by an inability of the heart to appropriately increase cardiac output during exertion. The cardiac diseases associated with symptoms of congestive failure include dilated cadiomyopathy, restrictive/constrictive cardiomyopathy, and hypertrophyic cardiomyopathy. Although patients with all three of these diseases present with the classical symptoms of shortness of breath, edema, and overwhelming fatigue, it is clear that the vast majority of patients presenting with failure have a dilated cardiomyopathy. Therefore, "congestive heart failure" (CHF) is generally considered equivalent to a dilated cardiomyopathy. Dilated cardiomyopathy patients have typical symptoms that are caused by both systolic as well as diastolic dysfunction, although the systolic dysfunction clearly predominates. In approximately half of the patients with dilated cardiomyopathy, the cause of the heart dysfunction is ischemic heart disease due to coronary atherosclerosis. That is, patients have had either a single myocardial infarction or multiple myocardial infarctions and the resultant scarring and remodeling has resulted in the development of a dilated and hypofunctional heart. In the remaining patients, the disease is referred to as idiopathic dilated cardiomyopathy as the causative agent remains undefined. Although modest differences exist between the patient with idiopathic (IDC) and ischemic (ISC) heart failure, they both share an abysmal prognosis and excessive morbidity and mortality. Indeed, patients with congestive heart failure have a one year survival of nearly 70% and a five year survival of only 20% after referral to a tertiary heart failure center. Morbidity is also significant as the average heart failure patient is hospitalized approximately two times each year with an average length of stay of greater than five days. Approximately half of all patients with congestive failure die suddenly--presumably due to a ventricular arrhythmia and sudden death, while the remaining patients die of worsening congestive failure.
Hemodynamically, the failing human heart demonstrates systolic dysfunction but also marked diastolic dysfunction. The diastolic dysfunction is thought to be due to abnormalities in two proteins that regulate the uptake of calcium into the sarcoplasmic reticulum storage pools, phospholamban and calcium-ATPase. Another hallmark of the development of the end-stage heart failure phenotype is maladaptive remodeling that includes: 1) cellular hypertrophy; 2) apoptosis; 3) interstitial infiltrates; 4) intesstitial fibrosis; 5) dilation of the ventricular cavity with thinning of the wall of the myocardium; and 6) occasional myocytes necrosis.
Since the primary abnormality in CHF is marked systolic dysfunction, investigators presumed that an inotropic agent, i.e., a drug that increases cardiac contractility, would benefit patients with heart failure. During the late 1960's and 1970's, a group of seminal studies elucidated the primary components of excitation contraction coupling in the heart. It was recognized that the most potent means of enhancing cardiac contractility both endogenously and exogenously was adrenegic stimulation. Beta-adrenergic receptors located on the cardiac sarcolemma coupled adrenergic agonists with the effector enzyme adenylyl cyclase via the guanine nucleotide-binding regulatory proteins. When activated, adenylyl cyclase produced the intracellular second messenger cyclic AMP with resultant activation of the promiscuous cell phosphorylator, protein kinase A. Once activated by cyclic AMP, protein kinase A phosphorylated the sarcolemmal gated calcium channel, the sarcoplasmic reticulum regulatory protein phospholamban, and the contractile protein troponin. Phosphorylation of these three proteins effected enhanced contractility via increased intracellular calcium levels and enhanced relaxation via facilitated uptake of calcium in the sarcoplasmic reticulum storage pools and decreased sensitivity to calcium due to phosphorylation of troponin. The second messenger signaling pathway could be attenuated by metabolism of cyclic AMP by the enzyme phosphodiesterase or alternatively by inhibiting receptor-G protein coupling through the receptor kinase Bark. Unfortunately, neither adrenergic agonists nor phosphodiesterase inhibitors proved beneficial in patients with congestive heart failure. In fact, large randomized and placebo-controlled clinical trials demonstrated an increase in mortality in patients treated with agents that as their major mechanism of action enhanced intracellular concentrations of cyclic AMP.
A second approach to increasing contractility has been the use of agents that increase the sensitivity of the contractile proteins to calcium. However, most inotropic agents of this class have also been associated with an increase in mortality.
At present, only one oral and three intravenous inotropic agents are approved for treatment of heart failure in the U.S. Digoxin, the only oral inotrope, was shown in a large randomized, double-blind and placebo controlled trial to have a neutral effect on survival in heart failure. However, there were concerns that it might have deleterious effects in some subgroups. milrinone, amrinone and dobutamine are beneficial in the acute therapy of congestive heart failure. However, chronic therapy with oral Milrinone or amrinone was associated with a marked increase in mortality. Similarly, chronic therapy with dobutamine has also been associated with increased mortality. All three of these intravenous agents augment contractility by increasing intracellular concentrations of cyclic AMP.
Another approach to the therapy of patients with congestive heart failure was based on the recognition that patients with congestive heart failure expressed a group of neurohormonal substances whose plasma concentrations could be inversely associated with morbidity and mortality in large populations of patients with CHF. These neurohormonal agent all share a common finding: when given in vivo or in vitro they can initiate an aladaptive remodeling of the heart and in some cases are cardiotoxic. Additionally, in experimental CHF models, they delay or attenuate the development of the heart failure phenotype.
The first neurohormonal agent to successfully serve as a therapeutic target was angiotensin II potent vasoconstrictor and activator of aldosterone. In the patient with CHF, this increase in blood volume and peripheral vascular resistance augments both preload and afterload resulting in further compromise of cardiac function. Indeed, studies have shown a direct relationship between increasing levels of angiotensin II (and/or renin) and cardiovascular mortality. Interestingly, transgenic mice that over-express angiotensinogen and therefore display elevated levels of angiotensin II demonstrate hypertension but do not have a phenotype consistent with congestive heart failure. Thus, it may be their effects on activating the bradykinin pathway or even an anti-adrenergic effect that is responsible for the beneficial effects of ACE inhibitors. Although angiotensin converting enzyme inhibitors have become a mainstay of therapy in patients with CHF and have been shown to be cost effective for long-term therapy, their overall impact on CHF has actuality been very modest, approximately a 18 to 22 percent decrease in mortality over four years.
In the early 1980's, there was first demonstrated a direct relationship between increasing levels of plasma catecholamines and mortality in patients with congestive failure. The fact that high levels of circulating catecholamines had pathophysiologic consequences was demonstrated by the finding that exposure of myocytes to chronic adrenergic stimulation resulted in cardiace remodeling with development of cardiac dilation and fibrosis. In addition, adrenergic activation caused abnormalities in receptor-effector coupling in the heart that replicated biochemical changes seen in the failing human heart: 1) marked down-regulation of the beta-adrenergic receptor; 2) uncoupling of the beta 2-adrenergic receptor from adenylyl cyclase; and 3) increased activity of the inhibitory G protein. Therefore, agonist-mediated abnormalities in receptor--G protein--adenylyl cyclase coupling explained the finding that the failing human heart was markedly insensitive to adrenergic drive. In a large multi-center trial of the beta-blocker metoprolol, there was no difference in survival in patients receiving active drug as versus those receiving placebo. However, there was a significant benefit when assessing the combined end-point of either death or the need for cardiac transplantation. As would be expected with an adrenergic blocker, the use of metoprolol was associated with a significant up-regulation of myocardial beta-adrenergic receptors. More recently, a group of clinical trials have assessed the use of carvedilol, a novel beta-adrenergic antagonist having vasodilator properties. Although the survival benefits of carvedilol were greater than those seen with the angiotensin converting enzyme inhibitors, metaanalysis of the U.S. trials included only 50 events. Therefore, the exact benefits on survival remain undefined. Beta-blockers are not easy to use in patients with CHF, as they require careful up-titration and cannot be utilized as rescue therapy. Carvedilol, for example, cannot be used for rescue therapy as it requires careful up-titration over a minimum of several weeks.
Additionally, there is an ongoing clinical trial with bucindolol, an agent that is very similar to carvedilol in that it has both beta blocking and vasodilator properties. Unlike carvedilol, bucindolol effects a significant up-regulation of receptor density and may therefore more accurately represent a "beta blocker." However, beta-blockers are difficult to utilize, and their mortality benefits remain unproven.
A more recent finding is that the proinflammatory cytokines are elevated in patients with congestive heart failure. Indeed, there is a direct relationship between elevated levels of TNF-.alpha. and II-6 and the degree of hemodynamic abnormalities. Similarly, the higher the TNF-.alpha. level the more severe the heart failure symptoms. Perhaps the most intriguing finding was that TNF-.alpha. is not expressed by normal human heart but is expressed in abundant amounts by human failing heart. Furthermore, TNF-.alpha. induces the expression of the proinflammatory cytokine II-1B. Either TNF-.alpha. or II-1B can recapitulate in vitro many of the biochemical and molecular biological abnormalities that characterize the failing human heart.
One anti-cytokine strategy that has been utilized in Phase I trials for the therapy of patients with CHF is subcutaneous administration of TNF-.alpha. soluble receptors (r75). This strategy was based on the assumption that soluble receptors would soak up free TNF-.alpha. thereby decreasing the amount of ligand that was available to the endogenous cell-surface receptors. However, difinitive assessment of this therapy requires a large multi-center controlled clinical trial. However, intuitively, the use of soluble receptors has several potential limitations: 1) the receptors can only be administered intravenously or subcutaneously; 2) other cytokines, i.e., IL-1b might also play a role in the cardiac pathophysiology of the inflammatory cytokines; 3) patients receiving long-term administration of TNF-.alpha. soluble receptors might be more susceptible to infectious or malignant diseased; and 4) intracellular cytokine expression might have important autocrine effects that are over and above the paracrine effects of the cytokines secreted by the myocytes.
A second strategy to inhibit TNF-.alpha. has utilized intravenous immuroglobulin IVIG) in an open-labeled clinical trial. IVIG has multiple properties including anticytokine effects. Its use was associated with significant improvements in ejection fraction and a suggestion of improved survival.
Perhaps the most intriguing possibility for the therapy of heart failure comes from recent studies assessing the effects of adenosine on myocardial cytokine production. Adenosine, a naturally occurring nucleotide, is expressed endogenously in mammals. At physiologic concentrations, adenosine substantially inhibits the ability of neonatal rat myocytes in culture to express TNF-.alpha. in response to lipopolysaccharide (LPS). This inhibitory response can be seen when adenosine is given before, during, or up to one hour after exposure to LPS and a similar effect is appreciable in isolated adult myocytes as well as in adult rat papillary muscle preparations. Pharmacologic testing suggests that the effects of adenosine on TNF-.alpha. inhibition are mediated via the A.sub.2 -adenosine receptor through stimulation of cyclic AMP since A.sub.2 agonists and cyclic AMP derivatives mimic but A.sub.2 -antagonists attenuate the anti-TNF-.alpha. effects. That adenosine-related modulation of TNF-.alpha. expression may have physiologic importance in humans comes from recent studies of cytokine expression in papillary muscle preparations isolated from failing human heart. At baseline, human hearts express abundant amounts of TNF-.alpha.. However, the level of expression can be increased as much as 10-fold by modest concentrations of LPS and this effect can be inhibited by adenosine. These anticytolcine effects would be expected to prevent the cytokine-medicated maladaptive remodeling in patients with myocardial damage and in so doing decrease the incidence of worsening heart failure and increase long-term survival.
U.S. Pat. No. 5,629,298, which is hereby incorporated herein by reference in its entirety, teaches that an A.sub.2 agonist increases the contractile performance of the heart. However, this teaching does not appreciate the use of adenosine analogs as a treatment for the repair and rehabilitation of diseased or damaged myocardial tissue.
U.S. Pat. No. 5,629,298 to Dobson teaches that administration of an adenosine A.sub.2 agonist, but not adenosine, can be used to increase the contractile performance of a compromised myocardium in a mammal. Dobson also attests that the use of adenosine A.sub.2 agonists in conjunction with a second compound which potentiates the beneficial effect of adenosine A.sub.2 receptor agonists, e.g., an adenosine transport inhibitor, an inhibitor of adenosine metabolism, or an adenosine A.sub.1 receptor antagonist would be beneficial for increasing contractile performance. Dobson proposes that the beneficial effects are the result of enhanced adenylyl cyclase activity in the presence of an A.sub.1 agonist. However, the basic teaching of Dobson and the rationales proposed for its use are inaccurate.